1.1 FIELD OF THE INVENTION
The present invention relates generally to the field of molecular biology. More particularly, certain embodiments comprise dopamine agonist compositions and methods for their use in the treatment of alcoholism and related compulsive disorders. In preferred embodiments methods and compositions are disclosed for the treatment of patients having the A1 allele of the D.sub.2 dopamine receptor (DRD2) gene.
1.2 DESCRIPTION OF THE RELATED ART
1.2.1 TREATMENT OF ALCOHOLISM
A variety of effective drugs are now available in the treatment of many mental afflictions including schizophrenia, anxiety reactions and affective disorders. In contrast, with the recent exception of naltrexone, vide infra, no current accepted pharmacotherapy exists for decreasing alcohol consumption and relapse in alcoholics (for reviews see Noble, 1984; Liskow and Goodwin, 1987; Litten and Allen, 1991; Gorelick, 1992).
A variety of methods have been described in the literature in recent years relating to treatment of chronic alcoholism. Such methods have included stimulating electroacupuncture of zones in the ears (Soviet Pat. No. SU 1,757,671, 1992); intramuscular injection of meksidol (Soviet Pat. No. SU 1,777,878, 1992); oral compositions which contain vitamin, protein, fat and carbohydrate compounds (Soviet Pat. No. SU 1,717,069, 1992); visual stimulation using pulsed red light (Soviet Pat. No. SU 1,699,467, 1991); peroral administration of vitamin complexes and honey (Soviet Pat. No. SU 1,697,802, 1991); intravenous injection of cholecystokinin (Soviet Pat. No. SU 1,463,302, 1989); administration of phenylalkanoyl amines (European Pat. No. EP 424,528, 1992); administration of opiod antagonists (Intl. Pat. Appl. Publ. No. WO 960947, 1996); administration of spiroindane derivatives (U.S. Pat. No. 5,298,622, 1994); application of low frequency alternating currents to reflect reflexogenic zones (Russian Pat. No. RU 2,056,110, 1996); a variety of homeopathic compositions including sulfur and rattlesnake venom (Russian Pat. No. RU 2,039,561, 1995); -apomorphine-teturam administration (Soviet Pat. No. SU 1,806,743, 1993); and a variety of treatment methods involving acute negative reaction and somatic disturbance (Soviet Pat. No. SU 170,148; 1968). Each of the aforementioned patents is specifically incorporated herein by reference in its entirety.
Although significant literature exists on the use of various compounds for the treatment of alcoholics, results to date have been sporadic, unpredictable, and a majority of the tests have been limited to theoretical considerations.
European Patent EP 0346830 and corresponding U.S. Pat. No. 4,882,335 (each specifically incorporated herein by reference) report the possible use of naltrexone and naloxone for the treatment of alcoholism in humans, although the data presented was limited to decreased drinking of alcohol by rats following administration of naloxone or naltrexone.
Intl. Pat. Appl. Publ. No. WO 9609047A1 (specifically incorporated herein by reference) discloses a method for treating alcoholism in a mammal using a combination of opioid antagonists and serotonin reuptake inhibitors.
However, with the burgeoning advances in the neurosciences and molecular genetics, the time is propitious to apply this cumulative knowledge to the effective treatment of alcoholism.
1.2.2 ALCOHOL AND THE DOPAMINERGIC SYSTEM
Alcohol, like other substances of abuse, induces euphoria and pleasurable feelings in users. It has been hypothesized that these positive reinforcement effects are manifested through activation of the mesolimbic dopaniinergic reward pathways of the brain (for reviews see Wise and Rompre, 1989; Koob, 1992). In support of this hypothesis is a substantial body of physiological, neurochemical, pharmacological and behavioral evidence. Thus, alcohol, administered both in vivo and in vitro, dose-dependently increases the firing rate of dopaminergic neurons in the ventral tegmental area (VTA) of the brain, indicating that the drug activates the mesoaccumbens dopaminergic system (Gessa et al., 1985; Brodie et al., 1990). These observations are consistent with several studies showing that low doses of systematically and locally administered ethanol increases dopamine (DA) release in a calcium-dependent manner from the nucleus accumbens (NAC) in awake rats (Imperato and Di Chiara, 1986; Wozniak et al., 1991; Yoshimoto et al., 1991; Weiss et al., 1993). That the dopaminergic system is implicated in alcohol-related behaviors also comes from brain lesion studies. Following circumscribed ablation of dopaminergic neurons within either the NAC or tuberculum olfactorium (TO), preference for ethanol significantly increased in rats (Quarfordt et al., 1991). The authors of this report (Quarfordt et al., 1991) suggest that one of the functional roles for the dopaminergic neurons of the NAC and TO is to regulate the craving for a drug with addictive liability such as ethanol.
A role for the dopaminergic system in ethanol preference is also suggested by data from animal genetic models of alcoholism. DA concentrations in the NAC of alcohol preferring (P) rats were found to be significantly lower when compared to alcohol non-preferring (NP) rats (Murphy et al., 1987; Gongwer et al., 1989). More recently, two independent studies of alcohol-naive P and NP rats have shown that the maximum number of binding sites (B.sub.MAX) of the D.sub.2 dopamine receptor to be significantly reduced in the NAC and caudate nucleus of P compared to NP rats (Stefanini et al., 1992; McBride et al, 1993). It is suggested (Stefanini et al., 1992) that one possible interpretation of the reduced D.sub.2 numbers in the P rats is that it may reflect a parallel reduction in dopaminergic neurotransmission in limbic areas of the brain. To compensate for this deficit, the P rats consume more alcohol in order to release enough DA to produce an adequate level of reward.
Whereas ethanol consumption involves several brain neurotransmitters including norepinephrine (Ahlenius et al., 1973; Amit and Brown, 1982; Brown and Amit, 1977; Corcoran et al., 1983; Davis et al., 1979; Murphy et al., 1985), serotonin (McBride et al., 1988; Murphy et al., 1988) and GABA (Hwang et al., 1990; McBride et al., 1990), growing evidence, derived from the administration of neurotransmitter receptor agonists and antagonists, further supports an important role for the dopaminergic system in mediating the stimulating reinforcing effects of ethanol.
1.2.3 DOPAMINE AGONISTS AND DECREASED ALCOHOL INTAKE IN RATS
Decreases in alcohol intake of P and High-Alcohol-Dinking (HAD) rats were found after the administration of the D.sub.2 agonists bromocriptine (McBride et al., 1990) and quinpirole (Dyr et al., 1993). In another study (Weiss et al., 1990), the differential effects of naloxone (an opiate antagonist), bromocriptine and methysergide (a 5-HT antagonist) on ethanol consumption was compared in P and unselected Wistar rats. In P rats, naloxone treatment resulted in a dose-dependent suppression in responding for both ethanol and water, but did not alter ethanol preference. This suggests that the response decrements observed with naloxone was reflective of a more general depression in consummatory behavior. In contrast, bromocriptine produced a significant, dose-dependent shift in preference from ethanol toward water by inhibiting responding for ethanol while enhancing water consumption. In the Wistar rats, naloxone and bromocriptine treatments produced changes in ethanol preference patterns similar to but less than those observed with methysergide. Furthermore, a recent study (Rassnick et al., 1993) has determined the effects of a novel dopamine receptor agonist (SDZ-205, 152) in rats trained to orally self-administer ethanol. The results of this study showed that administration of this dopamine agonist selectively reduced ethanol-reinforced responding without affecting responses for water.
1.2.4 APOMORPRINE AND ALCOHOL DEPENDENCE IN HUMANS
Studies of humans provide additional support to connections between alcohol dependence and CNS dopaminergic function. Neuroendocrine evidence for reduced dopamine receptor sensitivity in alcoholics has been found. Using apomorphine (APO), a D.sub.2 agonist, the maximal growth hormone (GH) response was found to be significantly reduced in alcoholics who were 2 months (Balldin et al., 1992) and more than 6 years (Balldin et al., 1993) abstinent compared to controls. It was suggested that the reduced D.sub.2 receptor function in alcoholics was a trait marker for this disorder, although the possibility that this reduction is acquired after earlier periods of heavy alcohol consumption cannot be ruled out. Heinz et al., (1995) compared GH response to APO in relapsed (active) and in abstinent (recovering) alcoholics. Despite the fact that both groups had similar prior alcohol consumption history and no other clinical data differentiated these groups, the relapsed alcoholics had a more blunted GH response compared to abstinent alcoholics. Additionally, Weisbeck et al. (1995) determined GH response to APO in controls and in alcoholics who were either family history positive or negative for alcoholism. The blunted response in the positive but not the negative group was significantly different when compared to controls. These authors suggest that the reduced D.sub.2 receptor function in family history positive alcoholics may be a genetically influenced trait marker. Finally, very recent imaging studies including PET (Hietela et al., 1994) and SPECT (Tiihonen et al., 1995) analyses have shown a reduced central dopaminergic function in chronic non-violent alcoholics compared to controls.
1.2.5 EARLY STUDIES USING BROMOCRIPTINE
At least three early studies (Morgan et al., 1980; Morgan, 1981; Anokhina, 1984) have investigated the use of bromocriptine for the treatment of alcoholism in humans, but the data were not controlled. In another study of 60 alcoholics, randomly assigned to bromocriptine (2.5 mg tid) or placebo, the bromocriptine group compared to the placebo group showed a greater amelioration of withdrawal symptoms over the 10-day trial (Borg and Weinholdt, 1982). In the first double-blind bromocriptine/placebo study, 50 alcoholics, randomly assigned to bromocriptine (2.5 mg tid, months 1-3; 5 mg tid, months 4-6) or placebo were evaluated for 6 months (Borg, 1983). The overall effects on the number and duration of drinking episodes, psychological status and social functioning were significantly improved in the bromocriptine compared to the placebo group. Rater global evaluation of medication effect was assessed as moderate to very beneficial in 16 of 19 bromocriptine administered patients and in one of 23 placebo administered patients. The incidence of adverse reactions was low in both groups, and the higher dose of bromocriptine (15 mg/day) was no better than the lower dose (7.5 mg/day) in treatment outcome. In a second double-blind controlled study (Dongier et al., 1991), 84 alcoholics received either bromocriptine (2.5 mg tid) or placebo and were followed for two months. Drinking behavior showed a marked improvement in both the bromocriptine and placebo treated groups. Moreover, significant differences in favor of the medication were observed in psychiopathological measures, and trends in the same direction in most of the other iffcacy measures.
In a third double-blind trial, alcoholics were given either bromocriptine (2.5 mg) tid, months 1-3; 5 mg tid, months 4-6) or placebo for six months (Powell et al., 1995). Alcoholics were divided, according to the authors, into three "not pure" subtypes: 1) "pure alcoholics," 2) alcoholics who had comorbid affective or anxiety disorders but not antisocial personality disorders (APD) and 3) alcoholics who had comorbid APD but were with or without Axis I disorders. Thirty-four alcoholics on bromocriptine and 31 alcoholics on placebo completed the trial. Analysis of data showed a significant decrease in anxiety (Beck Anxiety Inventory) and a trend in reduced craving and drinking days only in APD alcoholics receiving bromocriptine compared to APD alcoholics receiving placebo.
Thus while the early studies support a role for the use of bromocriptine in the treatment of certain aspects of alcoholism, relatively few patients were studied or remained in the trial, the reliability and validity of most of the measures used to assess outcome were not reported, and patient compliance to the bromocriptine schedule was not done.
1.2.6 OPIOIDERGIC AND DOPAMINERGIC SYSTEMS
There is growing evidence that the opioidergic and dopaminergic systems are anatomically and functionally interconnected. Nigrostriatal dopaminergic afferents have direct input into the opioidergic (enkephalinergic) neurons of the striatum (Kubota et al., 1986), and all detectable enkephalin neurons in the striatum contain the D.sub.2 dopamine receptor mRNA (Le Moine et a., 1990). Moreover, dopamine antagonists and lesions of the dopaminergic pathways in the brain affect preproenkephalin A activity (Morris et al., 1988; Normand et al., 1988).
Behavioral, pharmacological and neurochemical studies implicate the opioidergic and dopaminergic systems in the reinforcing effects of ethanol and other drugs of abuse (Koob and Bloom, 1988). Animal studies show that opiate receptor agonists increase preference for ethanol (Volpicelli et al., 1992; Wild and Reid, 1990), whereas antagonists of these receptors reduce ethanol consumption (Le et al., 1993; Myers et al., 1986). Further, studies on human alcoholics suggest the effectiveness of the opiate receptor antagonist naltrexone in reducing the positive reinforcing effects of alcohol consumption (O'Malley et al., 1992; Swift et al., 1985; Volpicelli et al., 1992). Moreover, ethanol-induced increase of brain doparnine levels in animals is blocked by both opiate receptor antagonists naloxone (Widdowson and Holman, 1992) and naltrexone (Benjamin et al., 1993). The gathering evidence suggests an essential role for the endogenous opioidergic system in mediating the effects of ethanol on brain dopamine pathways associated with reward.
1.2.7 NALTREXONE IN THE TREATMENT OF ALCOHOLISM
Lopez-Ibor-Alino (1990), in an uncontrolled naltrexone trial in an opiate treatment program, found that patients on regimens of naltrexone increased their alcohol use. In sharp contrast, however, other studies have shown the opposite effect. Volpicelli et al., (1992), in a double-blind, placebo-controlled trial, studied the effect of naltrexone in 70 male outpatient alcoholics. During the 12-week study, only 23% of naltrexone-treated subjects met the criteria of relapse, whereas 54.3% of the placebo-treated subjects relapsed. Moreover, subjects taking naltrexone reported significantly less alcohol craving and days in which any alcohol was consumed. In an accompanying article, O'Malley et al. (1992), also in a double-blind, placebo-controlled trial, studied 97 alcoholics receiving supportive therapy or coping skills therapy over a 12-week period. They found that naltrexone proved superior to placebo in measures of drinking and alcohol-related problems, including abstention rates, number of drinking days, relapse and severity of alcohol-related problems. Moreover, those patients who initiated drinking and who had received naltrexone and coping skills therapy were the least likely to relapse. Bohn et al. (1994) conducted a single-blind study with two doses of naltrexone and found reduced drinking by alcoholics.
Mason et al. (1994), in a double-blind, placebo-controlled pilot trial, studied the effects of nalmefene (a new opiate antagonist and structurally similar to naltrexone) in 21 alcoholics. Nalmefene lowered the rate of relapse and decreased the number of drinks/drinking days when compared to the placebo group. A very recent study by Volpicelli et al. (1995) presented data on their previously studied alcoholics (Volpicelli et al, 1992) who deviated from abstinence. Of the 36 subjects who reported a slip from abstinence, 12 naltrexone- and 17 placebo-treated alcoholics were available for assessment. The week of their first reported slip averaged around week 3 for both groups with no significant difference between the two groups. However, the placebo subjects drank more alcohol during the first lapse than did the naltrexone-treated subjects (P&lt;0.05). Moreover, retrospective self-reports showed that a significantly larger proportion of naltrexone than placebo subjects experienced less high than usual after drinking alcohol (P=0.006). However, the reported levels of uncoordination, alcohol craving, memory disturbance and loss of temper did not differ between the naltrexone and placebo groups. Moreover, there were no significant correlations between these subjective variables and whether the subjects drank until they met relapse criterion.
How naltrexone exerts its effects in humans remains yet to be determined. In a recent study, Swift et al. (1994) quantified the effects of naltrexone on alcohol intoxication in nonalcoholic humans. They found less positive reinforcement and more intense sedative effects when the subjects received naltrexone and ethanol as compared to subjects who received placebo and ethanol. The combination of naltrexone and ethanol also induced nausea and vomiting in some of the subjects. These findings are consistent with the idea that naltrexone alters the subjective effects of ethanol. In particular, naltrexone reduces the positive reinforcing effects of ethanol intoxication and increases the negative reinforcing effects. Swift et al. (1994) suggest that these changes may underlie the observed decrease in ethanol drinking reported in the above clinical trials.
The neurochemical mechanisms through which naltrexone exerts its effects in humans remain unclear. Whereas the above cited clinical studies suggest the involvement of the opioidergic system, there is a substantial body of evidence from animal studies which indicates a connection between the opioidergic and dopaminergic system in the brain. For example, a recent report by Benjamin et al. (1993) shows that naltrexone and other opioid antagonists block the ethanol-induced release of dopamine in animals. If then, as cited earlier, the positive reinforcing effects of ethanol (and other substances of abuse) are manifested through activation of the mesolimbic dopaminergic pathways of the brain, then naltrexone, by blocking ethanol-induced release of dopamine, may diminish the reinforcing effects of alcohol.
In 1990, the present inventor and colleagues reported (Blum et al., 1990) a molecular genetic association with alcoholism. Specifically, the A1 (minor) allele of the D.sub.2 dopamine receptor (DRD2) gene was found to be associated with severe alcoholics when compared to nonalcoholic controls. Subsequently, several studies, done in the U.S. and abroad, have further ascertained the role of this gene in alcoholism. Despite variations in the selection of subjects and other methodological issues, the combined evidence from these studies affirms the high prevalence of the A1 allele in alcoholics, especially when severe alcoholics are compared to nonalcoholic controls. Similarly, studies on cocaine addicts and polysubstance abusers have also found a high prevalence of the minor (A1 and B1) alleles of the DRD2 gene in these patients (Noble et al., 1993; Comings et al., 1991; Smith et al., 1992). Binding studies on the brains of deceased subjects showed that those carrying the A1 (minor) allele had reduced number of D.sub.2 receptors than those carrying the A2 (major) allele (Noble et al., 1991). Moreover, in recent neurophysiological Noble et al., 1994c) and neuropsychological (Berman and Noble, 1995) studies of alcohol- and other drug-naive children, evidence also suggests a reduced dopaminergic function in subjects carrying the A1 allele compared to those having only the A2 allele. Put together, the emerging data suggest that subjects who inherit the A1 allele have an inherent deficit of their brain dopaminergic system.
1.3 DEFICIENCIES IN THE PRIOR ART
Alcoholism, a heterogeneous disorder with hereditary and environmental determinants, is a major health and social problem with a high recidivism rate. With the exception of the aversive agent disulfiram, no accepted pharmacotherapy now exits for the treatment of this disorder. The advent of molecular genetic techniques makes possible the identification of genetic types of alcoholics. Such identification renders feasible specific pharmacogenetic approaches to the treatment of hereditary forms of alcoholism.
A need to effectively treat alcoholics has long been recognized. To this end, several workers have treated this group of patients with various drugs; some that cause an aversion to alcohol (e.g., Anabuse.RTM.) while more recent treatments have investigated drugs that act as dopamine agonists. While some success has been reported in treating alcoholics with bromocryptine, the results did not indicate that such treatment was generally suitable for all alcohol addiction. Apparently there has not yet been an effort to first identify those subsets of patients appropriate for treatment with dopamine agonists, nor have any efforts been made to tailor drugs to interact specifically with receptor molecules in alcoholic patients identified with a genetic predisposition to alcohol abuse. Additionally, as with many drug regimens, there is not only a lack of specificity for universal treatment of alcoholics, there is also the problem of drug side effects. This is particularly so in the reported attempts to treat alcoholism where the limited success with certain dopamine agonists can be associated with inappropriate effects and/or interactions with other drugs.